Clinical studies suggest the co-morbidity of functional pain syndromes such as irritable bowel syndrome (IBS), fibromyalgia, chronic pelvic pain and somatoform disorders approaches 40% to 60%. The incidence of episodic or persistent visceral pain associated with these "functional" disorders is two to three times higher in women than in men. One of the possible explanations for this phenomenon is the estrogen modulation of pain transmission. While a central site of this modulation has been shown previously, here we propose to study a peripheral site, the dorsal root ganglion (DRG). In DRG neurons, 17[unreadable]-estradiol (E2) rapidly inhibits intracellular calcium [Ca2+] flux induced by ATP, a putative nociceptive signal. Conversely, E2 also attenuates anti-nociceptive cellular responses to a [unreadable]-opioid receptor (MOP) agonist, implying that E2 may enhance cellular responses to nociceptive signals. This proposal, Estrogen Receptors Mediate Nociceptive Signaling in Primary Sensory Neurons in Female Mice, will test a general hypothesis that E2 acting on primary afferent nociceptors has both pro-nociceptive and anti-nociceptive effects depending on which signals converge upon DRG. First, the role of different estrogen receptors (ER) in E2 activation of purinergic (P2X) and vanilloid (TRPV1) receptors will be studied in wild type, estrogen receptor-a and estrogen receptor-[unreadable] knock-out mice. Second, since we hypothesize that E2 may act differently on visceral then on cutaneous nociceptors, we will compare the [Ca2+]i response to activation of P2X and TRPV1 receptors in retrograde-labeled visceral and cutaneous DRG neurons from knock-out and wild type mice. Third, E2 may negatively modulate opioid analgesia by interfering with MOP. Pharmacological manipulations will be used to determine how ER activation modulates Ca2+ channel and MOP functions. Receptor binding will determine if E2 alters the number and affinity of MOP in the DRG and the site-specific regulation of MOP coupling to G-proteins. Together these experiments will define a new site(s) and mechanism of E2 modulation of nociceptive signaling. Furthermore, they will provide important information about the action of E2 on primary sensory neurons for a better understanding of gender differences observed in the clinical presentation of functional pain-associated syndromes. Nociceptive systems are implicated in the etiology of functional disorders, which often are complicated by co-morbid depression, panic and other psychiatric disorders, all pose health risks. Designing new gender-specific therapies will have a major impact on health-related quality of life in patients with functional pain disorders, significantly reducing therapeutic interventions.